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WO2005063760A1 - C-8 LINKED PYRROLO[2,1-c][1,4]BENZODIAZEPINE-ACRIDONE/ACRIDINE HYBRIDS - Google Patents

C-8 LINKED PYRROLO[2,1-c][1,4]BENZODIAZEPINE-ACRIDONE/ACRIDINE HYBRIDS Download PDF

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WO2005063760A1
WO2005063760A1 PCT/IN2003/000464 IN0300464W WO2005063760A1 WO 2005063760 A1 WO2005063760 A1 WO 2005063760A1 IN 0300464 W IN0300464 W IN 0300464W WO 2005063760 A1 WO2005063760 A1 WO 2005063760A1
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Inventor
Ahmed Kamal
Olepu Srinivas
Poddutoori Ramulu
Gujjar Ramesh
Pogula Praveen Kumar
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Council of Scientific and Industrial Research CSIR
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Priority to PCT/IN2003/000464 priority patent/WO2005063760A1/en
Priority to JP2005512763A priority patent/JP4718328B2/en
Publication of WO2005063760A1 publication Critical patent/WO2005063760A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention provides novel pyrrolo-[2,l-c][l,4]benzodiazepine hybrids useful as anti-tumour agents.
  • the present invention also provides a process for the preparation of new pyrrolo[2,l-c][l,4]benzodiazepine hybrids as antitumour agents.
  • the present invention provides a process for the preparation of 7-methoxy-8-[n'- (4"-acridonylcarboxamido)alkyl]-oxy-( 11 aS) ⁇ 1,2,3,11 a-tetraydro-5H- ⁇ yrrolo [2, 1 -c] [l,4]benzodiazepin-5-one and 7-methoxy-8-[n'-(4"-acridinylcarboxamido)-alkyl]-oxy- (llaS)-l,2,3,lla-tetraydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one with aliphatic chain length variation of these compounds and it also describes the DNA binding, anticancer (antitumour) activity.
  • the structural formula of the novel pyrrolo[2,l-c]-[l,4]benzodiazepines of the invention is given below:
  • PBD dimers have been developed that comprises two C2-exo-methylene substituted DC-81 subunits tethered through their C ⁇ 8 position via an inert propanedioxy linker (Gregson, S. I; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. I; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737). Recently, a noncross- linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumour activitiy.
  • Naturally occurring pyrrolo[2,l-c][l,4]benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA.
  • the main object of the present invention is to provide new pyrrolo[2,l-c][l,4]- benzodiazepine hybrids useful as antitumour agents.
  • the compound of the invention is selected from the group consisting .of 7-Methoxy-8-[2'-(4"-acridonylcarboxamido)ethyl]-oxy-
  • Formula VII the process comprising reacting an acridone or an acridine acid with (2S)-N-[4-(n'- aminoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I
  • Formula V isolating the compound of formula Il/formula V and then reducing the compounds of formula Il/formula V with SnCl 2 .2H 2 O in presence of an organic solvent up to a reflux temperature, isolating the (2S)-N- ⁇ 4-[n'-(4"-acridonylcarboxamido)-alkyl]-oxy-5-methoxy-2- aminobenzoyl ⁇ pyrroU-dine-2-carboxaldehydediethylthioacetal of formula III/(2S)-N- ⁇ 4-[n'- (4"-acridinylcarbox-arm ⁇ o)-alkyl]-oxy-5-methoxy-2-aminobenzoyl ⁇ pyrroUdine-2- carboxaldehyde diethyl thioacetal of formula VI where n is 2-3 by known methods,
  • Formula HI Formula VI reacting compound of formula Ill/formula VI with a known deprotecting agents in a conventional manner to give novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IV/formula VII wherein n and R are as stated above.
  • the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan.
  • the compound of formula Il/formula V is isolated by washing with saturated NaHCO 3 , brine, drying and evaporation of the solvent.
  • the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol.
  • the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO 3 solution, diluting with ethyl acetate, filtering through ceUte and extracted an organic phase and drying the organic phase over Na 2 SO 4 .
  • the deprotecting agent used for obtaining the compound of formula IV/formula Nil comprises HgCl 2 and CaCO 3 in MeC ⁇ -water (4:1).
  • the process of the invention comprises reacting, an acridone or an acridine acid with (2S)- ⁇ -[4-(n'-ammoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I
  • the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan and the compound of formula Il/formula V is isolated by washing with saturated NaHCO 3 , brine, drying and evaporation of the solvent.
  • the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol and the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO 3 solution, diluting with ethyl acetate, filtering through celite and extracted an organic phase and drying the organic phase over Na 2 SO 4 .
  • the deprotecting agent used for obtaining the compound of formula IV/formula VII comprises HgCl 2 and CaCO 3 in MeCN-water (4: 1).
  • the precursors acridone acid (AtweU, G. J.; Cain, B. F.; Baguley, B. C; Finlay, G. J.; Denny, W. A. J. Med. Chem. 1984, 27, 1481), acridine acid (AtweU, G. J.; Rewcastle, G. W.; Baguley, B. C; Denny, W. A. J. Med Chem.
  • Example 2 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203g, 1.5 mmol) and HOBt(0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethylthioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 4 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(3'- aminopropyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.473 g, 5 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 6 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203- g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight.
  • Example 7 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and ⁇ OBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(3'-amino-propyl)oxy- 5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.457 g, 1 mmol) in DMF was added to it at same temperature and the solution was stirred at room-temperature for overnight.
  • IV 0 0 10 a One dose of IV at 10 molar concentration
  • formula IV has shown to possess ⁇ 10 nano molar potency (at the LC 50 level) against one melanoma cancer (UACC-62) and 0.1 micro molar potency against colon cancer (HCC- 2998), CNS cancer (SNB-75), breast cancer (MDA-MB-435) and also have ⁇ 10 micro molar potency against two melanoma cancer cell lines (LOXIMVI, M14) and one renal cancer (SN12C).
  • Table 2. logio GI50 logio TGI and logio LC50 mean graphs midpoints(MGJV ⁇ D) of in vitro cytotoxicity data for the compound IV against human tumour cell lines.
  • Each cancer type represents the average of six to nine different cancer ceU lines. 333NF/03 MEAN GRAPH

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Abstract

The present invention provides novel pyrrolo-[2,1-c][1,4]benzodiazepine of the formula given below wherein R is Hor OH and n is 2-3 ( formula (I) and (II) useful as anti-tumour agents and a process for the preparation thereof.

Description

C8 - LINKED PYRROLO[2,l-c][l,4]BENZODIAZEPINE-ACKIDONE/ACRIDINE HYBRIDS
Field of the invention The present invention provides novel pyrrolo-[2,l-c][l,4]benzodiazepine hybrids useful as anti-tumour agents. The present invention also provides a process for the preparation of new pyrrolo[2,l-c][l,4]benzodiazepine hybrids as antitumour agents. More particularly, the present invention provides a process for the preparation of 7-methoxy-8-[n'- (4"-acridonylcarboxamido)alkyl]-oxy-( 11 aS)~ 1,2,3,11 a-tetraydro-5H-ρyrrolo [2, 1 -c] [l,4]benzodiazepin-5-one and 7-methoxy-8-[n'-(4"-acridinylcarboxamido)-alkyl]-oxy- (llaS)-l,2,3,lla-tetraydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one with aliphatic chain length variation of these compounds and it also describes the DNA binding, anticancer (antitumour) activity. The structural formula of the novel pyrrolo[2,l-c]-[l,4]benzodiazepines of the invention is given below:
Figure imgf000002_0001
n = 2-3 R = H, OH
Background of the invention Pyrrolo[2,l-c][l,4]benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo[2,l-c][l,4]benzodiazepines (PBDs). These antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position ( unimoto, S.; Masuda, T.; Kanbayashi, N.; Hamada, M.; Naganawa, H. Miyamoto, M.; Takeuchi, T.; and Unezawa, H. J. Antibiot., 1980, 33, 665.; Kohn, K. W. and Speous, C. L. J. Mol. Biol., 1970, 51, 551.; Hurley, L. H.; Gairpla, C. and Zmijewski, M. Biochem. Biophys. Ada., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H. Biochmestry, 1981, 20, 7572). The molecules have a right-handed twist, which allows them to follow the curvature of the minor groove of B-form double-stranded DNA spanning three base pairs. A recent development has been the linking of two PBD units through their C-8 positions to give bisfunctional alkylating agents capable of cross-Unking DNA (Thurston, D. E.; Bose, D. S.; Thomson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C; Neidle, S. and Hurley, L. H. J. Org. Chem., 1996, 61, 8141).
Figure imgf000003_0001
DC-81 dimers (n= 3-5); DSB-120 (n= 3)
Figure imgf000003_0002
imine-amide PBD dimers; n = 3 - 5 Recently, PBD dimers have been developed that comprises two C2-exo-methylene substituted DC-81 subunits tethered through their C~8 position via an inert propanedioxy linker (Gregson, S. I; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. I; Jenkins, T. C; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737). Recently, a noncross- linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumour activitiy. (Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M. J. Med. Chem. 2002, 45, 4679). Naturally occurring pyrrolo[2,l-c][l,4]benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA. Examples of naturally occurring PBD's include anthramycin, DC-81, tomaymycin, sibiromycin and neothramycin. However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drug resistance and metaboUc inactivation. Objects of the invention The main object of the present invention is to provide new pyrrolo[2,l-c][l,4]- benzodiazepine hybrids useful as antitumour agents. Another objective of the present invention is to provide a process for the preparation of novel pyrrolo[2,l-c][l,4]-benzodiazepine hybrids useful as antitumour agents. Summary of the invention Accordingly the present invention provides novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IV or Nil wherein R = H, OH and n is 2-3.
Formula IV
Formula VII
Figure imgf000004_0001
n = 2-3 R = H, OH
In one embodiment of the invention, the compound of the invention is selected from the group consisting .of 7-Methoxy-8-[2'-(4"-acridonylcarboxamido)ethyl]-oxy-
(l laS)l,2,3,l la-tetra-hydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one; 7 - Methoxy - 8 -[
2' - (4" - acridonylcarboxamido) ethyl] - oxy - (4R) - hydroxy - (llaS) 1, 2, 3, 11a- tetrahydro - 5H - pyrrolo [2, 1-c] [1, 4] benzodiazepin - 5 - one; 7-Methoxy-8-[3'-(4"- acridonylcarboxamido)propyl]-oxy-(l 1 aS) 1 ,2,3 , 11 a-tetra-hydro-5H-pyrrolo[2, 1 -c] [1,4] benzodiazepin-5-one; 7-Methoxy-8-[3'-(4"-acridonylcarboxamido)propyl]-oxy-(4R)-hydroxy -(1 laS)l,2,-3,l la tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one; 7-Methoxy-8-[2'- (4"-acridinylcarboxamido)ethyl]-oxy-(l 1 aS) 1 ,2,3, 11 a-tetrahydro-5H-pyrrolo [2, 1 - c][l,4]benzodiazepin-5-one; 7-Methoxy-8-[2'-(4"-acridinylcarboxamido)ethyl]-oxy-(4R)- hydroxy-(l laS)l,2,3,-lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one; 7- methoxy - 8 - [3'-(4"-acridinylcarboxamido)propyl]-oxy-(l laS)l,2,3,lla-tetra-hydro-5H- pyrrolo[2, l-c][l,4]benzodiazepin-5-one and 7-Methoxy-8-[3'-(4"-acridinylcarboxamido) propyl]-oxy-(4R)-hydroxy-(l laS)l, 2,-3,1 la tetrahydro-5H-pyrrolo[2, l-e][l,4]benzodiazepin- 5-one. The present invention also provides a process for preparation of pyrrolo-[2,l- c][l,4]benzodiazepine hybrids of formula IN and Nil wherein R = Η, OΗ and n is 2-3,
Figure imgf000005_0001
Formula IV
Figure imgf000005_0002
Formula VII the process comprising reacting an acridone or an acridine acid with (2S)-N-[4-(n'- aminoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I
Figure imgf000005_0003
in the presence of EDCI and HOBt in organic solvent for a period of 24 h to obtain (2S)-N- {4-[n'-(4"-acrido-nylcarboxamido)-alkyl]-oxy-5-methoxy-2-nitrobenzoyl}pyrroUdine-2- carboxaldehyde diethyl thioacetal II / (2S)-N-{4-[n5-(4"-acridinylcarboxamido)-alkyl]-oxy-5- methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula V where 'n' is 2-3,
Figure imgf000006_0001
u Formula II
Figure imgf000006_0002
Formula V isolating the compound of formula Il/formula V and then reducing the compounds of formula Il/formula V with SnCl2.2H2O in presence of an organic solvent up to a reflux temperature, isolating the (2S)-N-{4-[n'-(4"-acridonylcarboxamido)-alkyl]-oxy-5-methoxy-2- aminobenzoyl}pyrroU-dine-2-carboxaldehydediethylthioacetal of formula III/(2S)-N-{4-[n'- (4"-acridinylcarbox-arm^o)-alkyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2- carboxaldehyde diethyl thioacetal of formula VI where n is 2-3 by known methods,
Figure imgf000006_0003
Formula HI
Figure imgf000007_0001
Formula VI reacting compound of formula Ill/formula VI with a known deprotecting agents in a conventional manner to give novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IV/formula VII wherein n and R are as stated above. In one embodiment of the invention, the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan. In another embodiment of the invention, the compound of formula Il/formula V is isolated by washing with saturated NaHCO3, brine, drying and evaporation of the solvent. In another embodiment of the invention the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol. In a further embodiment of the invention, the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO3 solution, diluting with ethyl acetate, filtering through ceUte and extracted an organic phase and drying the organic phase over Na2SO4. In another embodiment of the invention, the deprotecting agent used for obtaining the compound of formula IV/formula Nil comprises HgCl2 and CaCO3 in MeCΝ-water (4:1). Detailed description of the invention The present invention provides novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IN or Nil wherein R = H, OH and n is 2-3 and also provides a process for the preparation thereof. The process of the invention comprises reacting, an acridone or an acridine acid with (2S)-Ν-[4-(n'-ammoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I
Figure imgf000007_0002
Formula I in the presence of EDCI and HOBt in organic solvent for a period of 24 h to obtain (2S)-N- {4-[n'-(4"-acrido-nylcarboxamido)-alkyl]-oxy-5-methoxy-2-nitrobenzoyl}pyrrolidine-2- carboxaldehyde diethyl thioacetal II / (2S)-N-{4-[n'-(4"-acridinylcarboxamido)-alkyl]-oχy-5- methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula V where n is 2-3,
Figure imgf000008_0001
Formula II
Figure imgf000008_0002
Formula V The compound of formula Il/formula V is isolated and then reduced with SnCl2.2H2O in the presence of an organic solvent such as methanol up to a reflux temperature to obtain (2S)-N-{4-[n'-(4"-acridonylcarboxamido)-alkyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroli- dine-2-carboxaldehydediethylthioacetal of formula III/(2S)-N-{4-[n'-(4"-acridinylcarbox- amido)-alkyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula VI where n is 2-3. The compounds of formula Ill/formula VI are then isolated by conventional methods.
Figure imgf000008_0003
Formula III
Figure imgf000009_0001
Formula VI The compounds of formula Ill/formula VI with a known deprotecting agents in a conventional manner to give novel pyrrolo[2,l-c][l,4]benzodiazepine hybrids of formula IV/formula VII wherein n and R are as stated above
Formula IV
Formula VII
Figure imgf000009_0002
n = 2-3 R = H, OH The organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan and the compound of formula Il/formula V is isolated by washing with saturated NaHCO3, brine, drying and evaporation of the solvent. The organic solvent used during the reduction of compound of formula Il/formula V comprises methanol and the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO3 solution, diluting with ethyl acetate, filtering through celite and extracted an organic phase and drying the organic phase over Na2SO4. The deprotecting agent used for obtaining the compound of formula IV/formula VII comprises HgCl2 and CaCO3 in MeCN-water (4: 1). The precursors, acridone acid (AtweU, G. J.; Cain, B. F.; Baguley, B. C; Finlay, G. J.; Denny, W. A. J. Med. Chem. 1984, 27, 1481), acridine acid (AtweU, G. J.; Rewcastle, G. W.; Baguley, B. C; Denny, W. A. J. Med Chem. 1987, 30, 664) and (2S)-N-[4-(nD- aminoalkyloxy)-5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (Thurston, D. E.; Morris, S. J.; Hartley, J. A. Chem. Commun. 1996, 563-565) have been prepared by Uterature methods. Some representative compounds of formula IV/VTI present invention are given below
1. 7-Methoxy-8-[2'-(4"-acridonylcarboxamido)ethyl]-oxy-(l laS)l,2,3,l la-tetra-hydro- 5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
2. 7-Methoxy~8-[2'-(4"-acridonylcarboxamido)ethyl]-oxy-(4R)-hydroxy-(l laS)l,2,- 3,l la-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one 3. 7-Methoxy-8-[3'-(4"-acridonylcarboxamido)propyl]-oxy-(l laS)l,2,3,l la-tetra-hydro- 5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
4. 7-Methoxy-8-[3 '-(4"-acridonylcarboxamido)propyl]-oxy-(4R)-hydroxy-(l 1 aS) 1 ,2,- 3,11a tetrahydro-5H-pyrrolo[2, l-c][l,4]benzodiazepin-5-one
5. 7-Methoxy-8-[2'-(4"-acridinylcarboxamido)ethyl]-oxy-(l laS)l,2,3, 1 la-tetrahydro- 5H-pyrrolo[2, l-c][ 1 ,4]benzodiazepin-5-one
6. 7-Methoxy-8-[2,-(4"-acridinylcarboxamido)ethyl]-oxy-(4R)-hydroxy-(l 1 aS) 1,2,3,- lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one
7. 7-Methoxy-8-[3'-(4"-acridinylcarboxamido)propyl]-oxy-(l laS)l,2,3,l la-tetra-hydro- 5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one 8. 7-Methpxy-8-[3'-(4"-acridinylcarboxamido)propyl]-oxy-(4R)-hydroxy-(l laS)l,2,- 3,11a tetrahydro-5H-pyrrolo[2, l-c][l,4]benzodiazepin-5-one - These new analogues of pyrrolo[2,l-c][l,4]benzodiazepine hybrids linked at C-8 position have shown promising DNA binding activity and efficient anticancer activity in various cell lines. The molecules synthesized are of immense biological significance with potential sequence selective DNA-binding property. This resulted in design and synthesis of new congeners as illustrated in Scheme-l/Scheme-2, which comprise:
1. The ether linkage at C-8 position of DC-81 intermediates with acridone/acridine ring moiety.
2. Up to refluxing the reaction mixture for 12-48 h. . Synthesis of C-8 linked PBD antitumour antibiotic hybrid imines.
4. Purification by column chromatography using different solvents like ethyl acetate, hexane, dichloromethane and methanol. The reaction schemes are given below and are representative of the process of the invention.
Figure imgf000011_0001
Scheme 1
Figure imgf000012_0001
Scheme 2 The following examples are given by way of illustration and therefore should not be construed to the present Umit of the scope of invention. Example 1 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol) and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(2D-aminoethyl)-oxy- 5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (0.443 g, lmmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over siUcagel using ethylacetate/hexane (8:2) solvent to give compound (2S)-N-{4-[2'-(4"- acridonylcarboxamido)-ethyl]-oxy-5-methoxy-2-nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II as a yellow liquid. The compound (2S)-N-{4-[2'-(4"-acridonylcarboxamido)-ethyl]-oxy-5-methoxy-2- nitro-benzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II (0.664 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S)-N-{4-[2'-(4"- acridonylcarboxamido) - ethyl] - oxy - 5 - methoxy - 2 - aminobenzoyl} pyrrolidine - 2 - carboxaldehyde diethyl thioacetal III. A solution of compound (2S)-N-{4-[2'-(4"-acridonylcarboxamido)-ethyl]-oxy-5- methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III (0.634 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CΗ C -MeOH) to give compound 7- methoxy-8-[2' -(4"-acridonylcarboxamido)ethyl]-oxy-(l 1 aS) 1 ,2,3 , 11 a-tetrahydro-5H-ρyrrolo [2, l-c][l,4]benzodiazepin-5-one. Example 2 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203g, 1.5 mmol) and HOBt(0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethylthioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give (4R)- hydroxy-(2S)-N-{4-[2'-(4"-acridonylcarboxarnido)-ethyl]-oxy-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal II as a yellow Uquid. The compound (4R)-hydroxy-(2S)-N-{4-[2'-(4"-acridonylcarboxamido)-ethyl]-oxy-5- methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal II (0.680 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (4R)-hydroxy-(2S)-N- {4-[2'-(4"-acridonylcarboxamido)-ethyl]-oxy-5-methoxy-2-aminobenzoyl}-pyrrol-idine-2- carboxaldehyde diethyl thioacetal III. A solution of compound (4R)-hydroxy-(2S)-N-{4-[2'-(4"-acridonylcarboxamido)- ethyl]-oxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.650 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-methoxy-8-[2'-(4"-acridonylcarboxamido)-ethyl]-oxy-(4R)-hydroxy-
(llaS)l,2,3,-l la-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiaze-pin-5-one. Example 3 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol) and ΗOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5°C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(3'-aminopropyl)-oxy- 5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.457 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaΗCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[3'-(4"- acridonylcarboxamido)-propyl]-oxy-5-methoxy-2-nitro-benzoyl} pyrrolidine-2- carboxaldehyde diethyl thioacetal II as a yellow Uquid.
1H NMR (CDCI3) δ 1.20-1.50 (m, 6H), 1.60-2.20 (m, 6H), 2.60-2.80 (m, 4H), 3.10-3.3 (m, 2H), 3.65-3.8 (m, 5H), 4.20-4.30 (m, 2H), 4.55-4.70 (m, 1H), 4.8 (d, 1H), 6.75 (s, 1H), 7.15 (t, 1H), 7.25 (t, 1H), 7.35 (d, 1H), 7.50 (s, 1H), 7.58-7.63 (t, 1H), 7.9 (bs, 1H), 8.15 (d, 1H), 8.35 (d, 1H), 8.55 (d, 1H); 12.3 (bs, 1H), MS (FAB) 679 [M + H]+". The compound (2S)-N-{4-[3 '-(4"-acridonylcarboxamido)-propyl]-oxy-5-methoxy-2- nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II (0.678 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefuUy with saturated NaHCO3 solution, dUuted with ethyl acetate, filtered through ceUte and extracted. The combined organic phase was dried over Na2SO , and evaporated under vacuum to afford crude (2S)-N-{4-[3'-(4"-acridonylcarboxamido)-ρropyl]- oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III.
1H NMR (CDC13) δ 1.20-1.45 (m, 6H), 1.55-2.35 (m, 6H), 2.60-2.85 (m, 6H), 3.6 (s, 3H), 3.7-3.8 (m, 2H), 4.15-4.25 (m, 2H), 4.62-4.75 (m, 2H), 6.25 (s, 1H), 6.8 (s, 1H), 7.15-7.3 (m, 2H), 7.35 (d, 1H), 7.65-7.70 (t, 1H), 7.85 (bs, 1H), 8.05 (d, 1H), 8.35 (d, 1H), 8.65 (d, 1H); 12.3 (bs, 1H). A solution of compound (2S)-N-{4-[3'-(4"-acridonylcarboxamido)-propyl]-oxy-5- methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III (0.648 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was. evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7- methoxy-8-[3'-(4"-acridonylcarboxamido)propyl]-oxy-(llaS)l,2,3,lla-tetrahydro-5H- pyrf olo[2, 1 -c][l ,4]benzodiazepin-5-one. 1H NMR (CDC13) δ 1.20-1.30 ( , 2Η , 1.85-2.40 (m, 6H), 3.5-3.8 (m, 6H), 4.20-4.30 (m, 2H), 6.80 (s, 1H), 7.2-7.35 (m, 2H) 7.40 (d, 1H), 7.5 (s, 1H), 7.65 (d, 1H), 7.75 (t, 1H), 8.05 (d, 1H), 8.45 (d, 1H), 8.65 (d, 1H); 12.25 (bs, 1H), MS (FAB) 525 [M + Hf . Example 4 Compound acridone acid (0.239 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(3'- aminopropyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.473 g, 5 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give (4R)- hydroxy-(2S)-N-{4-[3'-(4"-acridonylcarboxamido)-propyl]-oxy-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal II as a yellow liquid. The compound (4R)-hydroxy-(2S)-N-{4-[3'-(4"-acridonylcarboxamido)-propyl]-oxy-
5-methoxy-2-nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II (0.694 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through ceUte and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (4R)-hydroxy-(2S)-N- {4-[3'-(4"-acridonylcarboxamido)-propyl]-oxy-5-methoxy-2-aminobenzoyl}pyrro-lidine-2- carboxaldehyde diethyl thioacetal III. A solution of compound (4R)-hydroxy-(2S)-N-{4-[3'-(4"-acridonylcarboxamido)- proρyl]-oxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.664 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was dUuted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-methoxy-8-[3'-(4"-acridonyl carboxamido) propyl]-oxy-(4R)-hydroxy-(l laS) 1,2,3,1 la-tetrahydro-5H-pyrrolo[2,l-e][l,4]benzodiaze pin-5-one. Example 5 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI
(0.203 g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5°C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(2'-aminoethyl)-oxy-5- methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (0.443 g, lmmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over silica gel using ethyl acetate/hexane (8:2) solvent to give compound (2S)-N-{4-[2'-(4"- acridinylcarboxamido)-ethyl]-oxy-5-methoxy-2-nitrobenzo-yl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II as a yellow Uquid. The compound (2S)-N-{4-[2'-(4"-acridinylcarboxamido)-ethyl]-oxy-5-methoxy-2- nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II (0.648 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefuUy with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S)-N-{4-[2'-(4"- acridinylcarboxamido)-ethyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III. A solution of compound (2S)-N-{4-[2'-(4"-acridinylcarboxamido)-ethyl]-oxy-5- methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III (0.618 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a ceUte bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7- methoxy-8-[2' -(4"-acridinylcarboxamido)ethyl]-oxy-(l 1 aS) 1 ,2,3 , 11 a-tetrahydro-5H-pyrrolo [2, 1 -c] [ 1 ,4]benzodiazepin-5-one. Example 6 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203- g, 1.5 mmol)and HOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(2'- aminoethyl)-oxy-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I (0.459 g, 1 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over sUica gel using ethyl acetate/hexane (8:2) solvent to give (4R)- hydroxy-(2ιS)-N-{4-[2'-(4"-acridinylcarboxamido)-ethyl]-oxy-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal II as a yellow liquid. The compound (4R)-hydroxy-(2S)-N-{4-[2'-(4"-acridinylcarboxamido)-ethyl]-oxy-5- methoxy-2-nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl • thioacetal II (0.664 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO , and evaporated under vacuum to afford the crude compound (4R)-hydroxy-(2iS)-N- {4-[2'-(4"-acridinylcarboxamido)-ethyl]-oxy-5-methoxy-2-aminobenzoyl}pyrro-lidine-2- carboxaldehyde diethyl thioacetal III. A solution of compound (4R)-hydroxy-(2S)-N-{4-[2'-(4"-acridinylcarboxamido)- ethyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III (0.634 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4: 1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a ceUte bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-methoxy-8-[2'-(4"-acridmylcarboxamido)-ethyl]-oxy-(4R)-hydroxy-(l 1 aS) 1,2, 3,-11 a-tetrahydro-5H-pyrrolo [2, 1 -c] [ 1 ,4]benzo diaze-pin-5 -one. Example 7 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), EDCI (0.203 g, 1.5 mmol)and ΗOBt (0.288 g, 1.5mmol) was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (2S)-N-[4-(3'-amino-propyl)oxy- 5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula I (0.457 g, 1 mmol) in DMF was added to it at same temperature and the solution was stirred at room-temperature for overnight. The mixture was washed with saturated NaΗCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over sUica gel Using ethyl acetate/hexane (8:2) solvent to give (2S)-N-{4-[2'-(4"-acridinylcarboxamido)- propyl]-oxy-5-methoxy-2-nitroben-zoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal II as a yellow liquid.
1H NMR (CDC13) δ 1.20-1.50 (m, 6H), 1.60-2.40 (m, 6H), 2.60-2.85 (m, 4H), 3.10-3.25 (m, 2H), 3.85-3.9 (m, 5H), 4.20-4.30 (m, 2H), 4.65-4.70 (m, 1H), 4.82 (d, 1H), 6.8(s, 1H), 7.4-7.8 ( , 4H), 7.85-8.05 (t, 2H), 8.10 (d, 1H), 8.82 (s, 1H), 8.95 (d, 1H); 11.9(bs, 1H), MS (FAB) 663 [M + H]+'. The compound (2S)-N-{4-[3 '-(4"-acridinylcarboxamido)-propyl]-oxy-5-methoxy-2- nitrobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal' II (0.662 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefuUy with saturated NaHCO3 solution, dUuted with ethyl acetate, filtered through ceUte and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (2S)-N-{4-[3'-(4"-acridi~ nylcarboxamido)-propyl]-oxy-5-methoxy-2-aminobenzoyl}pyrroUdine-2-carboxaldehyde diethyl thioacetal III. lH NMR (CDC ) δ 1.20-1.5 (m, 6H), 1.60-2.40 (m, 6H), 2.60-2.80 (m, 4H), 3.55-3.7 ( , 2H), 3.8 (s, 3H), 3.9-4.00 (m, 2H), 4.15-4.25 (m, 2H), 4.65-4.80 (m, 2H), 6.25 (s, IH), 6.8 (s, IH), 7.50-7.80 (m, 4H), 7.90-8.00 (m, 2H), 8.85 (s, IH), 8.95 (d, IH); 11.9 (bs, IH). A solution of compound (2S)-N-{4-[3-(4"-acridinylcarboxamido)-propyl]-oxy-5- methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.632 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO4). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7- methoxy-8-[3 ' -(4"-acridinylcarboxamido)propyl]-oxy-( 11 aS) 1 ,2,3 , 11 a-tetrahydro-5H-pyrrolo [2,l-c][l,4]benzodiazepin-5-one. 1H NMR (CDC13) δ 1.20-1.30 (m, 2Η), 1.95-2.45 (m, 6H), 3.5-3.8 (m, 5H), 4.25-4.45 (m, 3H), 6.80 (s, IH), 7.50-7.80 (m, 5H) 7.95-8.1 (m, 2H), 8.15 (d, IH), 8.90 (s, IH), 9.00 (d, IH); 12.00 (bs, IH), MS (FAB) 509 [M + H]+". Example 8 Compound acridine acid (0.223 g, 1 mmol) was taken in dry DMF (10 mL), (0.203 g, 1.5'mmol)and HOBt (0.288 g, 1.5mmol)was added and the mixture was cooled at 0-5 °C and the mixture was stirred for 30 min. A solution of (4R)-hydroxy-(2S)-N-[4-(3'-aminopropyl)- oxy-5-methoxy-2-nitrobenzoyl]pyrroUdine-2-carboxaldehyde diethyl thioacetal of formula 1(0.473 g, 5 mmol) in DMF was added to it at the same temperature and the solution was stirred at room temperature for overnight. The mixture was washed with saturated NaHCO3 (50 mL), brine, dried and solvent was evaporated. The crude material was chromatographed over siUca gel using ethyl acetate/hexane (8:2) solvent to give compound (4R)-hydroxy-(2S)- N-{4-[3'-(4"-acridinylcarboxarnido)-propyl]-oxy-5-methoxy-2-nitrobenzoyl}pyrroUdine-2- carboxaldehyde diethyl thioacetal II as a yellow liquid. The compound (4R)-hydroxy-(2S)-N-{4-[3 '-(4"-acridinylcarboxamido)-propyl]-oxy- 5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal II (0.678 g, 1 mmol) was dissolved in methanol (15 mL) and added SnCl2.2H2O (1.128 g, 5 mmol) was refluxed for 2 h or until the TLC indicated that reaction was completed. The reaction mixture was then adjusted to pH 8 carefully with saturated NaHCO3 solution, diluted with ethyl acetate, filtered through celite and extracted. The combined organic phase was dried over Na2SO4, and evaporated under vacuum to afford the crude compound (4R)-hydroxy-(2S)-N- {4-[3'-(4"-acridinylcarboxamido)-propyl]-oxy-5-methoxy-2-aminobenzoyl}pyrro-Udine-2- carboxaldehyde diethyl thioacetal III. A solution of compound (4R)-hydroxy-(2S)-N-{4-[3'-(4"-acridinylcarboxamido)- propyl]-oxy-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.648 g, 1 mmol), HgCl2 (0.8145 g, 3 mmol) and CaCO3 (0.3 g, 3 mmol) in MeCN-water (4:1) was stirred slowly at room temperature until TLC indicates complete loss of starting material. The reaction mixture was diluted with EtOAc (30 mL) and filtered through a celite bed. The clear yellow organic supernatant was extracted with saturated 5% NaHCO3 (20 mL), brine (20 mL) and the combined organic phase is dried (Na2SO ). The organic layer was evaporated in vacuum and purified by column chromatography (90% CH2Cl2-MeOH) to give compound 7-methoxy-8-[3'-(4"-acridinyl carboxamido) propyl]-oxy-(4R)-hydroxy-(l laS) 1,2,3, 1 la-tetrahydro-5H-pyrrolo[2, l-c]-[l,4]-benzodia-zepin-5-one.
Biological Activity: In vitro biological activity studies were carried out at National Cancer Institute (USA). Cytotoxicity: 7-methoxy-8-[3'-(4"-acridonylcarboxamido)propyl]-oxy-(l laS)l,2,3,l la- tetrahydr"o-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5-one.of formula IV was evaluated for primary anti-cancer activity (Table 1) and in vitro against sixty human tumour cells derived from nine cancer types (leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, prostate, and breast cancer). For each compound, dose response curves for each cell line were measured at a minimum of five concentrations at 10 fold dilutions. A protocol of 48 h continuous drug exposure was used and a sulforhodamine B (SRB) protein assay was used to estimate ceU viability or growth. The concentration causing 50% ceU growth inhibition (GI50), total cell growth inhibition (TGI 0% growth) and 50% cell death (LC50, -50% growth) compared with the control was calculated. The mean graph midpoint values of log^TGI and logι0LC50 as well as logio GI50 for IV are listed in Table 2. The mean graph itself is shown in Table 4. As demonstrated by mean graph pattern, compound IV exhibits an interesting profile of activity and selectivity for various cell lines. The mean graph mid point of logio TGI and log10 C50 showed similar pattern to the logio GI50 mean graph mid points. Table 1. In vitro one dose primary anticancer assay* acridone linked PBD hybrid of IV
PBD hybrid Growth percentages (Lung) (Breast) (CNS) NCI-H460 MCF7 SF-268
IV 0 0 10 aOne dose of IV at 10 molar concentration The novel pyrrolobenzodiazepine hybrid 7-methoxy-8-[3'-(4"-acridonylcarbo- xamido)-propyl]-oxy-(l laS)l,2,3,l la-tetrahydro-5H-pyrrolo[2,l-c][l,4]benzodiazepin-5- one. of formula IV has shown to possess <10 nano molar potency (at the LC50 level) against one melanoma cancer (UACC-62) and 0.1 micro molar potency against colon cancer (HCC- 2998), CNS cancer (SNB-75), breast cancer (MDA-MB-435) and also have <10 micro molar potency against two melanoma cancer cell lines (LOXIMVI, M14) and one renal cancer (SN12C). The LC50 values of nine cancers (average of six to nine cancer ceU lines) of compound 7-methoxy-8-[3'-(4"-acridonylcarboxamido)-propyl]-oxy-(l laS)l,2,3,l la- tetrahydro-5H-pyrrolo[2, l-c][l,4]benzodiazepin-5-one.of formula IV listed in Table 3. Table 2. logio GI50 logio TGI and logio LC50 mean graphs midpoints(MGJVΗD) of in vitro cytotoxicity data for the compound IV against human tumour cell lines.
Compound Logio GI50 Logio TGI Logio LC50 ___ __ __ __
Table 3. Log LC50 (concentration in mol L causing 50% lethality) Values for Compounds IV Cancer Compound IV Leukemia -4.00 non-small-cell lung -4.14 Colon -4.33 CNS -4.425 Melanoma -5.09 Ovarian -4.012 Renal -4.27 Prostate -4.00 Breast -4.40
Each cancer type represents the average of six to nine different cancer ceU lines. 333NF/03 MEAN GRAPH
Figure imgf000022_0001

Claims

im: Pyrrolo[2, l-c][l,4]benzodiazepine hybrid of the formula given below wherein R is H or OH and n is 2-3
Figure imgf000023_0001
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000023_0002
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000023_0003
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000023_0004
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000024_0001
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000024_0002
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000024_0003
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000024_0004
Pyrrolobenzodiazepine hybrid as claimed in claim 1 of the structure
Figure imgf000024_0005
A process for the preparation of a compound of the formula wherein R is H or OH and n is 2-3
Figure imgf000025_0001
the process comprising reacting reacting an acridone or an acridine acid with (2S)-N- [4-(n'-aminoalkyloxy)-5-methoxy-2-nitrobenzoyl]-pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I
Figure imgf000025_0002
in the presence of EDCI and HOBt in organic solvent for a period of 24 h to obtain
(2S)-N-{4-[n'-(4"-acrido-nylcarboxamido)-alkyl]-oxy-5-methoxy-2-nitrobenzoyl} pyrrolidine-2-carboxaldehyde diethyl thioacetal II / (2S)-N-{4-[n'-(4"- acridinylcarboxamido)-alkyl]-oxy-5-methoxy-2-nitrobenzoyl}pyrroUdine-2- carboxaldehyde diethyl thioacetal of formula V where 'n' is 2-3,
Figure imgf000025_0003
Formula II
Figure imgf000025_0004
Formula V isolating the compound of formula Il/formula V and then reducing the compounds of formula Il/formula V with SnCl2.2H2O in presence of an organic solvent up to a reflux temperature, isolating the (2S)-N-{4-[n'-(4"-acridonylcarboxamido)-alkyl]- oxy-5-methoxy-2-aminobenzoyl}pyrroli-dine-2-carboxaldehydediethylthioacetal of formula III/(2S)-N-{4-[n'-(4"-acridinylcarbox-amido)-alkyl]-oxy-5-methoxy-2- aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula VI where n is 2-3,
Figure imgf000026_0001
Formula HI
Figure imgf000026_0002
Formula VI reacting compound of formula Ill formula VI with a deprotecting agent to obtain the desired pyrrolo[2,l-c][l,4]benzodiazepine hybrid.
A process as claimed in claim 10 wherein the organic solvent used for the reaction of the acridone/acridine acid with compound of formula I comprises dimethyl furan.
A process as claimed in claim 10 wherein the compound of formula Il/formula V is isolated by washing with saturated NaHCO3, brine, drying and evaporation of the solvent.
A process as claimed in claim 10 wherein the organic solvent used during the reduction of compound of formula Il/formula V comprises methanol.
A process as claimed in claim 10 wherein the compound of formula Ill/formula V is isolated by adjusting the pH of the reaction mixture to about pH 8 with a saturated NaHCO3 solution, dUuting with ethyl acetate, filtering through celite and extracted an organic phase and drying the organic phase over Na2SO4.
15 A process as claimed in claim 10 wherein the deprotecting agent used for obtaining the compound of formula IV/formula VII comprises HgCl2 and CaCO3 in MeCN- water (4: 1).
16 A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula given below wherein R is H or OH and n is 2-3 and a pharmaceutically acceptable additive.
Figure imgf000027_0001
17 A method for the treatment of cancer in a subject suffering from the same comprising administering a pharmaceutically effective amount of a compound of the formula
Figure imgf000027_0002
wherein R is H or OH and n is 2-3. 18. A method as claimed in claim 17 wherein the patient is a mammal.
19. A method as claimed in claim 17 wherein the mammal is a human being,
20. A method as claimed in claim 17 wherein the cancer is selected from the group consisting of leukemia, non-small cell, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast.
1. Use of a compound of formula given below for the treatment of cancer selected from the group consisting of leukemia, non-small cell, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast in a subject suffering from the same.
Figure imgf000028_0001
PCT/IN2003/000464 2003-12-31 2003-12-31 C-8 LINKED PYRROLO[2,1-c][1,4]BENZODIAZEPINE-ACRIDONE/ACRIDINE HYBRIDS Ceased WO2005063760A1 (en)

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PCT/IN2003/000464 WO2005063760A1 (en) 2003-12-31 2003-12-31 C-8 LINKED PYRROLO[2,1-c][1,4]BENZODIAZEPINE-ACRIDONE/ACRIDINE HYBRIDS
JP2005512763A JP4718328B2 (en) 2003-12-31 2003-12-31 C8-linked pyrrolo [2,1-c] [1,4] benzodiazepine-acridone / acridine hybrid

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JP2009515870A (en) * 2005-11-10 2009-04-16 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ Novel pyrrolo [2,1-c] [1,4] benzodiazepine hybrids and methods for their preparation
WO2009016647A1 (en) * 2007-08-01 2009-02-05 Council Of Scientific & Industrial Research Pyrrolo [2,1-c][1, 4] benzodiazepine-glycoside prodrugs useful as a selective anti tumor agent
US11583590B2 (en) 2017-09-29 2023-02-21 Daiichi Sankyo Company, Limited Antibody-pyrrolobenzodiazepine derivative conjugate and method of use thereof for treating a tumor
US11628223B2 (en) 2017-09-29 2023-04-18 Daiichi Sankyo Company, Limited Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-α][1,4]diazepines
US12246196B2 (en) 2017-09-29 2025-03-11 Daiichi Sankyo Company, Limited Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-a][1,4]diazepines
US12350344B2 (en) 2017-09-29 2025-07-08 Daiichi Sankyo Company, Limited Methods of treating a tumor by administering a claudin-6 (CLDN6) or CLDN9 antibody-pyrrolobenzodiazepine derivative conjugate

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